Someone who readily detects one musk does not necessarily perceive every other odor strongly. A 2023 study found that a genetic form associated with detecting the musk compound muscone at lower concentrations was often inherited together with a form associated with weaker perception of β-ionone.
The starting question was why people differ so much in their perception of musks. The researchers focused on OR5AN1, an odorant receptor that responds to musks, examining cellular responses, perceived intensity and pleasantness, detection of faint odors, and relationships with neighboring receptor genes.
Musk is not the name of a single molecule
The musk odor character can be produced by multiple fragrance ingredients with different structures. The compounds studied included macrocyclic musks, which have large molecular rings, such as muscone, exaltolide, and ethylene brassylate, as well as the nitro musk musk ketone and the polycyclic musks galaxolide and tonalide.
The researchers first compared five major genetic forms of OR5AN1 in cultured cells. The common L289F form has a changed amino acid at position 289 in the receptor protein. This form showed larger maximum responses to five macrocyclic musks than the reference form.
By contrast, EC50, the concentration producing half the maximum response, did not differ clearly among the three forms that responded to these five macrocyclic musks. A larger cellular response and a response at a lower concentration are different properties. Maximum responses to musk ketone did not differ, and none of the tested OR5AN1 forms responded to galaxolide or tonalide.
Intensity differences appeared for some musks at some concentrations
The human evaluation used an existing dataset from 530 participants recruited in New York. From their assessments of 90 stimuli, the researchers extracted ratings for eight musks, each smelled at two concentrations. Intensity and pleasantness were ranked within each participant to reduce individual differences in scale use.
The main comparison involved 512 people: 68 with two reference copies, designated LL; 239 with one reference copy and one L289F copy, designated LF; and 205 with two L289F copies, designated FF.
FF participants rated ethylene brassylate, exaltolide, and galaxolide as more intense than LL participants at particular presentation concentrations. For a given molecule, the difference did not appear at both concentrations tested. No significant intensity differences were found for the other macrocyclic musks, and no significant genotype differences in pleasantness were established.
The finding therefore concerns associations between receptor genotype and the intensity of some musks. It should be distinguished from whether someone likes musk or perceives all musks as uniformly stronger.
Muscone differed in the concentration needed for detection
Muscone was one of the compounds for which the New York ratings showed no significant intensity difference. The researchers therefore tested detection thresholds across a wider concentration range in 54 people in Japan. There were 11 participants with two reference copies, 21 with one copy of each form, and 22 with two L289F copies.
Using 18 successive twofold dilutions, the researchers raised and lowered the concentration to determine the limit of detection. Each person’s threshold was the average of two measurements conducted at least one day apart.
FF participants could detect more dilute muscone than LL participants, with LF participants falling between them. Regression using genotype showed a significant association, with an adjusted R² of 14%. Comparing intensity at readily perceptible concentrations and finding the boundary of faint-odor detection can reveal individual differences in different ways.
A neighboring gene connected musk and β-ionone
The researchers next examined genes near OR5AN1. Their focus was OR5A1, a different odorant receptor that responds to β-ionone. In public genomic data from 2,504 people, the OR5AN1 form with the greater musk response tended to occur together with an OR5A1 form with a weaker response to β-ionone.
This relationship was examined in terms of genetic linkage: variants in nearby genes do not occur in completely independent combinations and can tend to be inherited together. It does not mean that a single receptor detects both musks and β-ionone.
The β-ionone intensity assessment in Japan also involved 54 people, but the participant composition differed from that of the muscone threshold experiment. Participants rated β-ionone and the reference odor butanol on seven-point scales. When the rating for butanol at a reference concentration was subtracted from the β-ionone rating, OR5AN1 FF participants perceived β-ionone as weaker than LL participants. The form associated with detecting more dilute muscone was thus associated with weaker ratings for β-ionone.
The authors suggest that individual differences for different odors are not necessarily entirely independent. However, these results cannot predict each person’s perception on a one-to-one basis. The paper also notes that high sensitivity to muscone does not invariably predict low sensitivity to β-ionone.
A genetic association does not always identify the detecting receptor
Galaxolide was associated with OR5AN1 genotype in human intensity ratings, yet did not activate OR5AN1 in cells. The researchers considered whether co-inheritance with variants of another nearby receptor gene might explain the apparent association with OR5AN1.
However, they could not confirm galaxolide responses in the neighboring receptors they tested, so this study did not identify the receptor directly responsible. People carrying rare reduced-function forms were also few, preventing adequate testing of whether these forms explain why some people perceive little or no musk.
These two points illustrate the value of combining statistical genetic associations, cellular function, and human perception. Checking each separately helps distinguish what has been explained from what still needs investigation.
Summary
The OR5AN1 L289F form produced larger maximum cellular responses to macrocyclic musks and was associated in humans with stronger perception of some musks and easier detection of dilute muscone. No corresponding significant differences in pleasantness were found.
This form also tended to occur with a weaker-response form of a different receptor for β-ionone and was associated with lower β-ionone intensity ratings. The simple phrase “a sensitive nose” encompasses odor-specific strengths and weaknesses, as well as connections between genes.
The research was supported by JSPS KAKENHI, the Japan Society for Bioscience, Biotechnology, and Agrochemistry, JST, the US NIH, and other sources. Takasago International Corporation supplied musk compounds, and T. Hasegawa supplied solvent. The authors declared no conflicts of interest.
Reference
Sato-Akuhara N, Trimmer C, Keller A, et al. Genetic variation in the human olfactory receptor OR5AN1 associates with the perception of musks. Chemical Senses. 2023;48:bjac037. doi:10.1093/chemse/bjac037.
